Interlaboratory evaluation of embryotoxicity in the postimplantation rat embryo culture

Piersma, Aldert H.; Attenon, Patrick; Bechter, R.; Govers, Mirjam J.A.P.; Krafft, Nathalie; Schmid, B.; Stadler, Jeanne; Verhoef, Aart; Verseil, Christian

doi:10.1016/0890-6238(95)00009-y

Cited by 38 publications

(20 citation statements)

References 15 publications

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“…In various studies, the usefulness of the rat whole embryo culture for in vitro embryotoxicity testing has been investigated (Cicurel & Schmid 1988;Piersma et al 1995Piersma et al & 1996. In these studies, comparisons were made between in vitro results and in vivo data.…”

Section: Discussionmentioning

confidence: 99%

“…This system can be used to detect developmental effects of compounds on the isolated intact embryo during a developmentally critical 48 hr period (Schmid 1985; Bechter & Schö n 1988;Piersma et al 1995Piersma et al & 1996. For the interpretation of results of in vitro embryotoxicity testing, the nature of the effects observed and the lowest effective compound concentration are essential.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

Beekhuijzen

Verhoef

Klaassen

et al. 2000

Pharmacology & Toxicology

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Abstract:The rat whole embryo culture was compared to an in vivo experiment with regard to embryotoxicity as well as exposure characteristics, using phenytoin as a model compound. Intra-embryonic concentrations and their embryotoxic effects were determined on gestation day 11 after in vitro administration of 50-150 mg/ml or in vivo gavage of 500-1500 mg/kg body-weight on gestation day 10. In addition, exposure kinetics were studied in vivo after a single oral dose on gestation day 10, and developmental defects on gestation day 21 were scored. The embryotoxic effects observed on gestation day 11 were more pronounced after in vitro exposure in comparison to in vivo exposure at similar intra-embryonic concentrations. Exposure of phenytoin on gestation day 10 in vitro via the culture medium resulted in general embryotoxicity on gestation day 11, whereas in vivo effects as determined on gestation day 11 were minimal. Plasma concentrations of phenytoin increased and plateaued around 35 mg/ml during the 48 hr monitoring period. Plasma concentration curves and pharmacokinetic parameters did not show remarkable differences between the dose groups, indicating that absorption is the limiting factor at the dose range used. Although the developmental effects were minimal as observed in vivo on gestation day 11, specific malformations (defects encompassing the urogenital, craniofacial and skeletal systems) were observed on gestation day 21. These findings show that with similar intra-embryonic concentrations of phenytoin the embryotoxicity in rat whole embryo culture was not comparable with the in vivo embryotoxicity as determined on gestation day 11. This discrepancy may at least partly be explained by differences in exposure characteristics.In embryotoxicity testing the in vitro test with closest resemblance to in vivo complexity available is the rodent whole embryo culture (New 1978). This system can be used to detect developmental effects of compounds on the isolated intact embryo during a developmentally critical 48 hr period (Schmid 1985; Bechter & Schö n 1988;Piersma et al. 1995Piersma et al. & 1996. For the interpretation of results of in vitro embryotoxicity testing, the nature of the effects observed and the lowest effective compound concentration are essential. As in vitro systems necessarily represent a small part of the living animal, extrapolation of these findings to the in vivo situation is not straightforward.The present study was carried out to compare an embryo culture experiment with an in vivo experiment in the rat with regard to exposure and effect characteristics, using phenytoin as a model compound. In man, phenytoin causes growth retardation, microcephaly, mental deficiency and craniofacial anomalies, known as the foetal hydantoin syndrome (Hanson & Smith 1975). Growth retardation and craniofacial defects have been produced in mice and rats in vivo (Lorente et al. 1981;Rowland et al. 1990; Finnell & Dansky 1991) and in embryo culture (Bruckner et al. 1983;Lindhout et al. 1987;Ozolins et al. 1995). T...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

Beekhuijzen

Verhoef

Klaassen

et al. 2000

Pharmacology & Toxicology

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“…An interlaboratory validation study is currently ongoing (Van Maele-Fabry et al 1991;Govers et al 1988;Piersma et al 1994). Results of an intersystem validation study have been published by Kucera et al 1993.…”

Section: Mammalian Postimplantation Whole Embryo Culturementioning

confidence: 95%

“…In an internal prospective validation study, ongoing for the last 10 years, with so far 5 in vivo teratogenic and 49 in vivo non-teratogenic compounds, the specificity of the test system was 90%, the sensitivity 60% and over all accuracy 87% (Bechter 1994, unpublished results). " Interlab validation (Govers et al 1988 andPiersma et al 1994). 0 Internal prospective validation (Bechter 1994, data not published).…”

Section: Mammalian Postimplantation Whole Embryo Culturementioning

confidence: 98%

The Validation and Use of In Vitro Teratogenicity Tests

Bechter

1995

Archives of Toxicology

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“…Because the test is difficult to standardize, it has been used succcessfully in only a few laboratories. The whole embryo culture assay underwent several standardization and validation trials in Europe (63). For a given group of structurally related chemicals, the whole embryo culture assay can be used inhouse for screening purposes.…”

Section: Hematopoietic Systemmentioning

confidence: 99%

13th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC): alternative testing methodologies for organ toxicity.

Spielmann

Bochkov

Costa

et al. 1998

Environ Health Perspect

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In the past decade in vitro tests have been developed that represent a range of anatomic structure from perfused whole organs to subcellular fractions. To assess the use of in vitro tests for toxicity testing, we describe and evaluate the current status of organotypic cultures for the major target organs of toxic agents. This includes liver, kidney, neural tissue, the hematopoietic system, the immune system, reproductive organs, and the endocrine system. The second part of this report reviews the application of in vitro culture systems to organ specific toxicity and evaluates the application of these systems both in industry for safety assessment and in government for regulatory purposes. Members of the working group (VWG) felt that access to high-quality human material is essential for better use of in vitro organ and tissue cultures in the risk assessment process. Therefore, research should focus on improving culture techniques that will allow better preservation of human material. The WG felt that it is also important to develop and make available relevant reference compounds for toxicity assessment in each organ system, to organize and make available via the Internet complete in vivo toxicity data, including human data, containing dose, end points, and toxicokinetics. The WG also recommended that research should be supported to identify and to validate biological end points for target organ toxicity to be used in alternative toxicity testing strategies.

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Interlaboratory evaluation of embryotoxicity in the postimplantation rat embryo culture

Cited by 38 publications

References 15 publications

Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

Comparison of in vitro and in vivo Developmental Toxicity and Pharmacokinetics of Phenytoin in the Rat

The Validation and Use of In Vitro Teratogenicity Tests

13th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC): alternative testing methodologies for organ toxicity.

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